Functional Connectomics of the Neocortical Microcircuit The cortex constitutes the primary site of higher cognitive functions and mental disease. No unified theory of how the cortex works exists yet, due to our basic ignorance about its microcircuits (i.e. the detailed connectivity patterns of any cortical area), and also because it is likely that its function is based on an emergent level, determined by the states of activity of large neuronal ensembles. Two-photon calcium imaging and photo-activation techniques enable us to simultaneous record and optically manipulate the activity of larger neuronal populations, while maintaining single cell resolution. Using such techniques we have encountered signs of what could be a highly distributed and essentially random cortical microcircuit. Based on these results, we propose the idea that the cortex is a random circuit, meaning that each synaptic connection is chosen by chance, independently from others. These circuits, mathematically analogous to completely connected ones, would maximize the distribution of information and enable the appearance of emergent functional states. This model runs contrary to the traditional view of the cortex, one that arose from sampling individual neurons, as a very specific machine where the connectivity and function of each neuron is precisely determined. Using this award, I want to test the hypothesis that the cortex is a random network, applying novel two-photon methods in a large-scale and systematic study of the mouse cortical microcircuit. I propose a three-pronged approach: 1- Image the activity of an entire cortical module in a mouse, to detect all spikes from all cells. 2- Perform a ?Circuit Cracker? analysis to obtain the blueprint of connectivity of the module. 3- Optically manipulate the population activity to test whether it behaves as a random circuit. Experiments will be done in mouse cortex in vivo, with awake, head-restrained preparations, under sensory stimulation and rest. Transgenic strains will be used to selectively label identified subpopulations of cells, and several cortical areas will be examined to explore common modular features. The proposed work will provide, for the first time, a complete description of the activity of any neural circuit and the blueprint of the cortical circuit and will pioneer ?Functional Connectomics?, i.e., deciphering the connectivity of the circuit from its functional correlations. If the data confirm that the microcircuit is indeed random, our results could also usher in a novel model for cortical function, one based on the existence of emergent functional states. This model could replace the current paradigm, and enable a more efficient understanding of the pathophysiology of cortical diseases, such as epilepsy and schizophrenia.